5-141574114-C-T

Position:

chr5-141574114-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005219.5(DIAPH1):c.1736G>A(p.Arg579His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,613,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 0 hom. )

Consequence

DIAPH1
NM_005219.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 0.674

Variant links:

Genes affected

DIAPH1 (HGNC:2876): (diaphanous related formin 1) This gene is a homolog of the Drosophila diaphanous gene, and has been linked to autosomal dominant, fully penetrant, nonsyndromic sensorineural progressive low-frequency hearing loss. Actin polymerization involves proteins known to interact with diaphanous protein in Drosophila and mouse. It has therefore been speculated that this gene may have a role in the regulation of actin polymerization in hair cells of the inner ear. Alternatively spliced transcript variants encoding distinct isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

DIAPH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050908625).

BP6

Variant 5-141574114-C-T is Benign according to our data. Variant chr5-141574114-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 194639.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=5}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00117 (178/152048) while in subpopulation NFE AF= 0.00163 (111/67986). AF 95% confidence interval is 0.00139. There are 0 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 178 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIAPH1	NM_005219.5 linkuse as main transcript	c.1736G>A	p.Arg579His	missense_variant	16/28	ENST00000389054.8	NP_005210.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIAPH1	ENST00000389054.8 linkuse as main transcript	c.1736G>A	p.Arg579His	missense_variant	16/28	5	NM_005219.5	ENSP00000373706	A2	O60610-1
DIAPH1	ENST00000518047.5 linkuse as main transcript	c.1709G>A	p.Arg570His	missense_variant	15/27	5		ENSP00000428268	P4	O60610-3
DIAPH1	ENST00000647433.1 linkuse as main transcript	c.1736G>A	p.Arg579His	missense_variant	16/29			ENSP00000494675	A2
DIAPH1	ENST00000647330.1 linkuse as main transcript	c.*963G>A		3_prime_UTR_variant, NMD_transcript_variant	15/15			ENSP00000494308

Frequencies

GnomAD3 genomes

AF:

0.00117

AC:

178

AN:

151930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000532

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00360

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00163

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00109

AC:

271

AN:

249466

Hom.:

AF XY:

0.00113

AC XY:

153

AN XY:

135352

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000319

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00264

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.00165

GnomAD4 exome

AF:

0.00143

AC:

2085

AN:

1461840

Hom.:

Cov.:

AF XY:

0.00136

AC XY:

992

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00221

Gnomad4 NFE exome

AF:

0.00167

Gnomad4 OTH exome

AF:

0.00124

GnomAD4 genome

AF:

0.00117

AC:

178

AN:

152048

Hom.:

Cov.:

AF XY:

0.00124

AC XY:

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.000531

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00360

Gnomad4 NFE

AF:

0.00163

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00147

Hom.:

Bravo

AF:

0.000835

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00131

AC:

ExAC

AF:

0.00114

AC:

138

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00158

EpiControl

AF:

0.00148

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 04, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	DIAPH1: BP4 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 17, 2020	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 14, 2017

p.Arg579His in exon 16 of DIAPH1: This variant is not expected to have clinical significance because it has been identified in 0.17% (210/126644) of European c hromosomes and in 0.28% (71/25790) of Finnish chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs182139018). In addition, computational prediction tools and conservation analyses suggest that the p.Arg579His variant may not impact the protein. -

Autosomal dominant nonsyndromic hearing loss 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

DIAPH1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 09, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant nonsyndromic hearing loss 1;C5567650:Progressive microcephaly-seizures-cortical blindness-developmental delay syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.082

T;.;T;.;T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.61

T;T;T;T;T;T

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0051

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;.;.;.;.

MutationTaster

Benign

1.0

N;N;N;N;N;N;N;N

PrimateAI

Benign

0.46

PROVEAN

Benign

0.35

N;.;.;N;N;N

REVEL

Benign

0.026

Sift

Benign

0.12

T;.;.;T;T;T

Sift4G

Benign

0.55

T;.;T;T;T;T

Polyphen

0.31

B;.;.;.;.;.

Vest4

0.12

MVP

0.42

MPC

0.14

ClinPred

0.0096

GERP RS

3.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over